CXCL16通过调节GPX1介导的抗氧化水平促进头颈部鳞状细胞癌增殖

何茹; 江弘毅; 张铖驰; 陈源; 刘文顺; 邓欣悦; 朱骁拯; 刘云业; 郑传铭; 张怡宁; 邵程莹; 段艳婷; 徐加杰

doi:10.1631/jzus.B2400192

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CXCL16通过调节GPX1介导的抗氧化水平促进头颈部鳞状细胞癌增殖

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Research Article | Updated：2025-04-21

CXCL16通过调节GPX1介导的抗氧化水平促进头颈部鳞状细胞癌增殖
CXCL16 promotes proliferation of head and neck squamous cell carcinoma by regulating GPX1-mediated antioxidant levels
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2025年26卷第1期页码：92-106
Affiliations：

1.Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China
2.College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, China
3.Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China
4.Department of Postgraduate Education, Jinzhou Medical University, Jinzhou 121000, China
5.The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China
6.Zhejiang Key Laboratory of Precision Medicine Research on Head & Neck Cancer, Hangzhou 310014, China
Funds：

the Scientific Research Fund of the National Health Commission-Zhejiang Provincial Health Major Science and Technology Plan Project(WKJ-ZJ-2415);the Key Research and Development Program of Zhejiang Province(2024C03166);the Traditional Chinese Medicine Science and Technology Project of Zhejiang Province(2022ZB020);the Zhejiang Provincial Natural Science Foundation of China(LY21H160049)
DOI：10.1631/jzus.B2400192
中图分类号：
CSTR：
收稿日期：2024-04-15，

修回日期：2024-07-29，

网络出版日期：2024-09-30，

纸质出版日期：2025-01-15
Accepted：

何茹,江弘毅,张铖驰等.CXCL16通过调节GPX1介导的抗氧化水平促进头颈部鳞状细胞癌增殖[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(01):92-106.

Ru HE, Hongyi JIANG, Chengchi ZHANG, et al. CXCL16 promotes proliferation of head and neck squamous cell carcinoma by regulating GPX1-mediated antioxidant levels[J]. Journal of zhejiang university-science b (biomedicine & biotechnology), 2025, 26(1): 92-106.
何茹,江弘毅,张铖驰等.CXCL16通过调节GPX1介导的抗氧化水平促进头颈部鳞状细胞癌增殖[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(01):92-106. DOI： 10.1631/jzus.B2400192.

Ru HE, Hongyi JIANG, Chengchi ZHANG, et al. CXCL16 promotes proliferation of head and neck squamous cell carcinoma by regulating GPX1-mediated antioxidant levels[J]. Journal of zhejiang university-science b (biomedicine & biotechnology), 2025, 26(1): 92-106. DOI： 10.1631/jzus.B2400192.

摘要

大量研究表明，CXC基序趋化因子配体16（CXCL16）在癌症中的高表达与预后不良以及肿瘤细胞的增殖、迁移和侵袭有关。虽然CXCL16可以作为肿瘤生物标志物，但其调节头颈部鳞状细胞癌（HNSCC）的潜在机制尚不清楚。在本研究中，我们旨在研究CXCL16在HNSCC中的表达，并揭示其潜在的生物学机制。我们在癌症基因组图谱（TCGA）数据库、本中心医院HNSCC患者的组织样本和HNSCC细胞系中均检测到CXCL16的高表达。实验结果表明，CXCL16敲低可抑制HNSCC细胞的增殖、迁移和侵袭。转录组测序显示，CXCL16可能通过调节谷胱甘肽过氧化物酶1（GPX1）的抗氧化途径影响HNSCC细胞生长。si-CXCL16细胞中活性氧（ROS）的水平升高，可能与抑制细胞增殖、迁移和侵袭有关。此外，与si-CXCL16组相比，si-CXCL16和GPX1抑制剂Eldecalcitol（ED-71）协同作用组能显著抑制HNSCC细胞的生长。综上，CXCL16可通过调节GPX1介导的抗氧化途径促进HNSCC细胞的发展。因此，靶向细胞CXCL16表达可能是治疗HNSCC的一个候选策略。

Abstract

Numerous studies have demonstrated that the high expression of CXC motif chemokine ligand 16 (CXCL16) in cancer correlates with poor prognosis

as well as tumor cell proliferation

migration

and invasion. While CXCL16 can serve as a tumor biomarker

the underlying mechanism in modulating head and neck squamous cell carcinoma (HNSCC) remains unclear. In this study

the aimed was to investigate the CXCL16 expression in HNSCC and to uncover the potential underlying mechanism. Hereby

we determined the high expression of CXCL16 in The Cancer Genome Atlas (TCGA) database

as well as in tissue samples from patients with HNSCC at our central hospital and from HNSCC cell lines. The results showed that

CXCL16

knockdown inhibited the proliferation

migration

and invasion of HNSCC cells. Mechanistically

transcriptome sequencing revealed that CXCL16 may affect HNSCC cell growth by regulating the antioxidant pathway of glutathione peroxidase 1 (GPX1). The reactive oxygen species (ROS) levels were elevated in small interfering CXCL16 (si-CXCL16) cells

which may contribute to the inhibition of cell proliferation

migration

and invasion. Moreover

treatment of cells with the GPX1 inhibitor eldecalcitol (ED-71) revealed that HNSCC cell growth was significantly inhibited in the synergistic group of si-CXCL16 and GPX1 inhibitor compared to the si-CXCL16 group. In conclusion

CXCL16 contributed to the development of HNSCC cells by modulating the GPX1-mediated antioxidant pathway. Thus

targeting cellular CXCL16 expression seems to be a promising strategy for treating HNSCC.

关键词

Keywords

references

Abel S , Hundhausen C , Mentlein R , et al. , 2004 . The transmembrane CXC-chemokine ligand 16 is induced by IFN-γ and TNF-α and shed by the activity of the disintegrin-like metalloproteinase ADAM10 . J Immunol , 172 ( 10 ): 6362 - 6372 . https://doi.org/10.4049/jimmunol.172.10.6362 https://doi.org/10.4049/jimmunol.172.10.6362

Becker TM , Juvik JA , 2016 . The role of glucosinolate hydrolysis products from brassica vegetable consumption in inducing antioxidant activity and reducing cancer incidence . Diseases , 4 ( 2 ): 22 . https://doi.org/10.3390/diseases4020022 https://doi.org/10.3390/diseases4020022

Bray F , Ferlay J , Soerjomataram I , et al. , 2018 . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries . CA Cancer J Clin , 68 ( 6 ): 394 - 424 . https://doi.org/10.3322/caac.21492 https://doi.org/10.3322/caac.21492

Brockstein B , Haraf DJ , Rademaker AW , et al. , 2004 . Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience . Ann Oncol , 15 ( 8 ): 1179 - 1186 . https://doi.org/10.1093/annonc/mdh308 https://doi.org/10.1093/annonc/mdh308

Chalabi-Dchar M , Cassant-Sourdy S , Duluc C , et al. , 2015 . Loss of somatostatin receptor subtype 2 promotes growth of KRAS-induced pancreatic tumors in mice by activating PI3K signaling and overexpression of CXCL16 . Gastroenterology , 148 ( 7 ): 1452 - 1465 . https://doi.org/10.1053/j.gastro.2015.02.009 https://doi.org/10.1053/j.gastro.2015.02.009

Cho SW , Kim YA , Sun HJ , et al. , 2016 . CXCL16 signaling mediated macrophage effects on tumor invasion of papillary thyroid carcinoma . Endocr Relat Cancer , 23 ( 2 ): 113 - 124 . https://doi.org/10.1530/ERC-15-0196 https://doi.org/10.1530/ERC-15-0196

Collado A , Marques P , Escudero P , et al. , 2018 . Functional role of endothelial CXCL16/CXCR6-platelet-leucocyte axis in angiotensin II-associated metabolic disorders . Cardiovasc Res , 114 ( 13 ): 1764 - 1775 . https://doi.org/10.1093/cvr/cvy135 https://doi.org/10.1093/cvr/cvy135

Dequanter D , Dok R , Koolen L , et al. , 2017 . Prognostic sig nificance of glutathione peroxidase levels (GPx1) in head and neck cancers. Front Oncol , 7 : 84 . https://doi.org/10.3389/fonc.2017.00084 https://doi.org/10.3389/fonc.2017.00084

Fan S , Tang QL , Lin YJ , et al. , 2011 . A review of clinical and histological parameters associated with contralateral neck metastases in oral squamous cell carcinoma . Int J Oral Sci , 3 ( 4 ): 180 - 191 . https://doi.org/10.4248/IJOS11068 https://doi.org/10.4248/IJOS11068

Gao ZR , Ling XY , Shi CY , et al. , 2022 . Tumor immune checkpoints and their associated inhibitors . J Zhejiang Univ-Sci B (Biomed & Biotechnol) , 23 ( 10 ): 823 - 843 . https://doi.org/10.1631/jzus.B2200195 https://doi.org/10.1631/jzus.B2200195

Griffith JW , Sokol CL , Luster AD , 2014 . Chemokines and chemo

kine receptors: positioning cells for host defense and immunity . Annu Rev Immunol , 32 : 659 - 702 . https://doi.org/10.1146/annurev-immunol-032713-120145 https://doi.org/10.1146/annurev-immunol-032713-120145

Guan JZ , Xu X , Qiu G , et al. , 2023 . Cellular hierarchy framework based on single-cell/multi-patient sample sequencing reveals metabolic biomarker PYGL as a therapeutic target for HNSCC . J Exp Clin Cancer Res , 42 : 162 . https://doi.org/10.1186/s13046-023-02734-w https://doi.org/10.1186/s13046-023-02734-w

Han J , Fu RJ , Chen C , et al. , 2021 . CXCL16 promotes gastric cancer tumorigenesis via ADAM10-dependent CXCL16/CXCR6 axis and activates Akt and MAPK signaling pathways . Int J Biol Sci , 17 ( 11 ): 2841 - 2852 . https://doi.org/10.7150/ijbs.57826 https://doi.org/10.7150/ijbs.57826

Hattermann K , Gebhardt H , Krossa S , et al. , 2016 . Transmembrane chemokines act as receptors in a novel mechanism termed inverse signaling . eLife , 5 : e10820 . https://doi.org/10.7554/eLife.10820 https://doi.org/10.7554/eLife.10820

Hsieh CY , Lin CC , Huang YW , et al. , 2022 . Macrophage secretory IL-1β promotes docetaxel resistance in head and neck squamous carcinoma via SOD2/CAT-ICAM1 signaling . JCI Insight , 7 ( 23 ): e157285 . https://doi.org/10.1172/jci.insight.157285 https://doi.org/10.1172/jci.insight.157285

Hu WD , Liu Y , Zhou WH , et al. , 2014 . CXCL16 and CXCR6 are coexpressed in human lung cancer in vivo and mediate the invasion of lung cancer cell lines in vitro . PLoS ONE , 9 ( 6 ): e99056 . https://doi.org/10.1371/journal.pone.0099056 https://doi.org/10.1371/journal.pone.0099056

Huang C , Ding GY , Gu CY , et al. , 2012 . Decreased selenium-binding protein 1 enhances glutathione peroxidase 1 activity and downregulates HIF-1α to promote hepatocellular carcinoma invasiveness . Clin Cancer Res , 18 ( 11 ): 3042 - 3053 . https://doi.org/10.1158/1078-0432.CCR-12-0183 https://doi.org/10.1158/1078-0432.CCR-12-0183

Izquierdo MC , Martin-Cleary C , Fernandez-Fernandez B , et al. , 2014 . CXCL16 in kidney and cardiovascular injury . Cytokine Growth Factor Rev , 25 ( 3 ): 317 - 325 . https://doi.org/10.1016/j.cytogfr.2014.04.002 https://doi.org/10.1016/j.cytogfr.2014.04.002

Jiang YY , Guo HY , Tong T , et al. , 2022 . lncRNA lnc-POP1-1 upregulated by VN1R5 promotes cisplatin resistance in head and neck squamous cell carcinoma through interaction with MCM5 . Mol Ther , 30 ( 1 ): 448 - 467 . https://doi.org/10.1016/j.ymthe.2021.06.006 https://doi.org/10.1016/j.ymthe.2021.06.006

Karaki S , Blanc C , Tran T , et al. , 2021 . CXCR6 deficiency impairs cancer vaccine efficacy and CD8 + resident memory T-cell recruitment in head and neck and lung tumors . J Immunother Cancer , 9 ( 3 ): e001948 . https://doi.org/10.1136/jitc-2020-001948 https://doi.org/10.1136/jitc-2020-001948

Kassab RB , Elhenawy AA , AbdulrahmanTheyab , et al. , 2023 . Modulation of inflammatory, oxidative, and apoptotic stresses mediates the renoprotective effect of daidzein against glycerol-induced acute kidney injury in rats . Environ Sci Pollut Res Int , 30 ( 56 ): 119016 - 119033 . https://doi.org/10.1007/s11356-023-30461-4 https://doi.org/10.1007/s11356-023-30461-4

Khan P , Fatima M , Khan MA , et al. , 2022 . Emerging role of chemokines in small cell lung cancer: road signs for metastasis, heterogeneity, and immune response . Semin Cancer Biol , 87 : 117 - 126 . https://doi.org/10.1016/j.semcancer.2022.11.005 https://doi.org/10.1016/j.semcancer.2022.11.005

Kim MJ , Sun HJ , Song YS , et al. , 2019 . CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer . Sci Rep , 9 : 13288 . https://doi.org/10.1038/s41598-019-49613-z https://doi.org/10.1038/s41598-019-49613-z

Korbecki J , Bajdak-Rusinek K , Kupnicka P , et al. , 2021 . The role of CXCL16 in the pathogenesis of cancer and other diseases . Int J Mol Sci , 22 ( 7 ): 3490 . https://doi.org/10.3390/ijms22073490 https://doi.org/10.3390/ijms22073490

Lei FJ , Chiang JY , Chang HJ , et al. , 2023 . Cellular and exosomal GPx1 are essential for controlling hydrogen peroxide balance and alleviating oxidative stress in hypoxic glioblastoma . Redox Biol , 65 : 102831 . https://doi.org/10.1016/j.redox.2023.102831 https://doi.org/10.1016/j.redox.2023.102831

Lepore F , D'Alessandro G , Antonangeli F , et al. , 2018 . CXCL16/CXCR6 axis drives microglia/macrophages phenotype in physiological conditions and plays a crucial role in glioma . Front Immunol , 9 : 2750 . https://doi.org/10.3389/fimmu.2018.02750 https://doi.org/10.3389/fimmu.2018.02750

Liu H , Yang ZJ , Lu WP , et al. , 2020 . Chemokines and chemokine receptors: a new strategy for breast cancer therapy . Cancer Med , 9 ( 11 ): 3786 - 3799 . https://doi.org/10.1002/cam4.3014 https://doi.org/10.1002/cam4.3014

Liu HY , Wang GQ , Wu T , et al. , 2022 . Efficacy and safety of eldecalcitol for osteoporosis: a meta-analysis of randomized controlled trials . Front Endocrinol (Lausanne) , 13 : 854439 . https://doi.org/10.3389/fendo.2022.854439 https://doi.org/10.3389/fendo.2022.854439

Livak KJ , Schmittgen TD , 2001 . Analysis of relative gene expression data using real-time quantitative PCR and the <math id="M2"><msup><mrow><mn mathvariant="normal">2</mn></mrow><mrow><mo>-</mo><mi mathvariant="normal">Δ</mi><mi mathvariant="normal">Δ</mi><msub><mrow><mi mathvariant="normal">C</mi></mrow><mrow><mi mathvariant="normal">T</mi></mrow></msub></mrow></msup></math> https://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=77595667&type= 2.53999996 https://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=77595657&type= 6.77333355 method . Methods , 25 ( 4 ): 402 - 408 . https://doi.org/10.1006/meth.2001.1262 https://doi.org/10.1006/meth.2001.1262

Lu YP , Kou YY , Gao Y , et al. , 2023 . Eldecalcitol inhibits the progression of oral cancer by suppressing the expression of GPx-1 . Oral Dis , 29 ( 2 ): 615 - 627 . https://doi.org/10.1111/odi.14010 https://doi.org/10.1111/odi.14010

Ma YS , Xu X , Luo M , 2017 . CXCR6 promotes tumor cell proliferation and metastasis in osteosarcoma through the Akt pathway . Cell Immunol , 311 : 80 - 85 . https://doi.org/10.1016/j.cellimm.2016.11.001 https://doi.org/10.1016/j.cellimm.2016.11.001

Matloubian M , David A , Engel S , et al. , 2000 . A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo . Nat Immunol , 1 ( 4 ): 298 - 304 . https://doi.org/10.1038/79738 https://doi.org/10.1038/79738

Matsushita K , Toiyama Y , Tanaka K , et al. , 2012 . Soluble CXCL16 in preoperative serum is a novel prognostic marker and predicts recurrence of liver metastases in colorectal cancer patients . Ann Surg Oncol , 19 ( Suppl 3 ): 518 - 527 . https://doi.org/10.1245/s10434-011-1993-8 https://doi.org/10.1245/s10434-011-1993-8

Mei XY , Qi DS , Zhang T , et al. , 2020 . Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects . EMBO Mol Med , 12 ( 3 ): e9469 . https://doi.org/10.15252/emmm.201809469 https://doi.org/10.15252/emmm.201809469

Mei Z , Huang JW , Qiao B , et al. , 2020 . Immune checkpoint pathways in immunotherapy for head and neck squamous cell carcinoma . Int J Oral Sci , 12 : 16 . https://doi.org/10.1038/s41368-020-0084-8 https://doi.org/10.1038/s41368-020-0084-8

Moloney JN , Cotter TG , 2018 . ROS signalling in the biology of cancer . Semin Cell Dev Biol , 80 : 50 - 64 . https://doi.org/10.1016/j.semcdb.2017.05.023 https://doi.org/10.1016/j.semcdb.2017.05.023

Moreira D , Sampath S , Won H , et al. , 2021 . Myeloid cell-targeted STAT3 inhibition sensitizes head and neck cancers to radiotherapy and T cell-mediated immunity . J Clin Invest , 131 ( 2 ): e137001 . https://doi.org/10.1172/JCI137001 https://doi.org/10.1172/JCI137001

Pei J , Pan XY , Wei GH , et al. , 2023 . Research progress of glutathione peroxidase family (GPX) in redoxidation . Front Pharmacol , 14 : 1147414 . https://doi.org/10.3389/fphar.2023.1147414 https://doi.org/10.3389/fphar.2023.1147414

Richardsen E , Ness N , Melbø-Jørgensen C , et al. , 2015 . The prognostic significance of CXCL16 and its receptor C-X-C chemokine receptor 6 in prostate cancer . Am J Pathol , 185 ( 10 ): 2722 - 2730 . https://doi.org/10.1016/j.ajpath.2015.06.013 https://doi.org/10.1016/j.ajpath.2015.06.013

Ruffin AT , Li H , Vujanovic L , et al. , 2023 . Improving head and neck cancer therapies by immunomodulation of the tumour microenvironment . Nat Rev Cancer , 23 ( 3 ): 173 - 188 . https://doi.org/10.1038/s41568-022-00531-9 https://doi.org/10.1038/s41568-022-00531-9

Saddawi-Konefka R , O'Farrell A , Faraji F , et al. , 2022 . Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC . Nat Commun , 13 : 4298 . https://doi.org/10.1038/s41467-022-31941-w https://doi.org/10.1038/s41467-022-31941-w

Siegel RL , Miller KD , Jemal A , 2020 . Cancer statistics, 2020 . CA Cancer J Clin , 70 ( 1 ): 7 - 30 . https://doi.org/10.3322/caac.21590 https://doi.org/10.3322/caac.21590

Siu LL , Even C , Mesía R , et al. , 2019 . Safety and efficacy of durvalumab with or without tremelimumab in patients with PD-L1-low/negative recurrent or metastatic HNSCC: the phase 2 CONDOR randomized clinical trial . JAMA Oncol , 5 ( 2 ): 195 - 203 . https://doi.org/10.1001/jamaoncol.2018.4628 https://doi.org/10.1001/jamaoncol.2018.4628

Tang YC , Hsiao JR , Jiang SS , et al. , 2021 . c-MYC-directed NRF2 drives malignant progression of head and neck cancer via glucose-6-phosphate dehydrogenase and transketolase activation . Theranostics , 11 ( 11 ): 5232 - 5247 . https://doi.org/10.7150/thno.53417 https://doi.org/10.7150/thno.53417

Tsai CF , Chen GW , Chen YC , et al. , 2022 . Regulatory effects of quercetin on M1/M2 macrophage polarization and oxidative/antioxidative balance . Nutrients , 14 ( 1 ): 67 . https://doi.org/10.3390/nu14010067 https://doi.org/10.3390/nu14010067

Wu W , Geng ZX , Bai HR , et al. , 2021 . Ammonium ferric citrate induced ferroptosis in non-small-cell lung carcinoma through the inhibition of GPX4-GSS/GSR-GGT axis activity . Int J Med Sci , 18 ( 8 ): 1899 - 1909 . https://doi.org/10.7150/ijms.54860 https://doi.org/10.7150/ijms.54860

Zhang GS , Wang Q , Qi XL , et al. , 2022 . OShnscc: a novel user-friendly online survival analysis tool for head and neck squamous cell carcinoma based on RNA expression profiles and long-term survival information . J Zhejiang Univ-Sci B (Biomed & Biotechnol) , 23 ( 3 ): 249 - 257 . https://doi.org/10.1631/jzus.B2100512 https://doi.org/10.1631/jzus.B2100512

Zhao YJ , Wang H , Zhou JD , et al. , 2022 . Glutathione peroxidase GPX1 and its dichotomous roles in cancer . Cancers (Basel) , 14 ( 10 ): 2560 . https://doi.org/10.3390/cancers14102560 https://doi.org/10.3390/cancers14102560

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